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WO2013008253A2 - Formulations d'imatinib - Google Patents

Formulations d'imatinib Download PDF

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Publication number
WO2013008253A2
WO2013008253A2 PCT/IN2012/000488 IN2012000488W WO2013008253A2 WO 2013008253 A2 WO2013008253 A2 WO 2013008253A2 IN 2012000488 W IN2012000488 W IN 2012000488W WO 2013008253 A2 WO2013008253 A2 WO 2013008253A2
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WO
WIPO (PCT)
Prior art keywords
imatinib
formulation
pharmaceutically acceptable
stable pharmaceutical
pharmaceutical formulation
Prior art date
Application number
PCT/IN2012/000488
Other languages
English (en)
Other versions
WO2013008253A3 (fr
Inventor
Suresh KONATHAM
Madhusudan MALLADI
Prasad Vure
Moumita BISWAS
Rahul BHISE
Ramesh KOTA
Original Assignee
Dr. Reddys Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddys Laboratories Limited filed Critical Dr. Reddys Laboratories Limited
Priority to IN1009CHN2014 priority Critical patent/IN2014CN01009A/en
Publication of WO2013008253A2 publication Critical patent/WO2013008253A2/fr
Publication of WO2013008253A3 publication Critical patent/WO2013008253A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • aspects of the present application relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects relate to processes for preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient.
  • the drug having the adopted name "imatinib mesylate” has a chemical name 4-[(4-Methyl1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]- phenyl]benzamide methanesulfonate, and its structural formula is shown below.
  • Imatinib mesylate has the empirical formula C 2 9H 3 iN70 « CH 4 S03 and its molecular weight is 589.7.
  • Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. It is soluble in aqueous buffers at pH ⁇ 5.5, but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.
  • Imatinib is a small molecule kinase inhibitor, used for the treatment of chronic myeloid leukemia (CML), Ph+ acute lymphoblastic leukemia, myelodysplastic/ myeloproliferative diseases (MDS/MPD), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), dermatofibrosarcoma protuberans (DFSP), and gastrointestinal stromal tumors (GIST).
  • CML chronic myeloid leukemia
  • MDS/MPD myelodysplastic/ myeloproliferative diseases
  • ASM aggressive systemic mastocytosis
  • HES hypereosinophilic syndrome
  • CEL chronic eosinophilic leukemia
  • DFSP dermatofibrosarcoma protuberans
  • GIST gastrointestinal stromal tumors
  • Imatinib mesylate is the active ingredient in products sold as GLEEVECTM for oral administration, in film-coated tablets containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base, in US.
  • imatinib mesylate is sold as GLIVECTM for oral administration, which is available as tablet dosage forms containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base.
  • Imatinib is also available as GLIVECTM hard gelatin capsules in some European countries, each capsule containing 50 mg or 100 mg imatinib mesylate.
  • doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.
  • U.S. Patent No. 5,521 ,184 discloses imatinib and the use thereof, especially as an anti-tumor agent.
  • U.S. Patent No. 6,894,051 discloses various polymorphic forms of imatinib or its salts.
  • International Application Publication Nos. WO 2007/136510, WO 2011/023146 and WO 2011/157450 disclose polymorphic forms of imatinib or its salts, amorphous form and processes for their preparation.
  • Form a and form ⁇ Two different crystalline forms of anhydrous imatinib mesylate, form a and form ⁇ , are known in the art.
  • Form a has a lower melting enthalpy than form ⁇ , which indicates an enantiotropic relationship between both forms.
  • Form ⁇ is the more stable polymorph at 25°C and 50°C, but at high temperatures Form ⁇ is converted to Form a. Both polymorphs show similar aqueous solubility characteristics.
  • the ⁇ form is thermodynamically stable and shows a suitable morphology with respect to flow properties.
  • imatinib mesylate Apart from Polymorph a and ⁇ , other polymorphic forms of imatinib mesylate are also known in the art, such as, a2, F, G, H, I, K, Delta, Epsilon, and H1. Two amorphous forms of imatinib mesylate are also known in the art.
  • WO 2003/090720 discloses high drug load tablets comprising imatinib or a pharmaceutically acceptable salt thereof in an amount from about 30% to 80% in weight of the active moiety based on the total weight of the tablet, but they are all produced by conventional wet granulation technique. According to said disclosure, the preferable hardness and abrasion resistance of the tablet and a sufficient bioavailability of the active ingredient can only be achieved by wet granulation, wherein imatinib mesylate preferably being used in the beta crystalline form.
  • U.S. Patent No. 7,943,172 discloses dry granulation processes of preparation of film-coated tablets comprising imatinib mesylate in alpha crystalline form wherein tablet cores and granule cores contain the active ingredient in proportions of 25% by weight to 80% by weight, based on the total weight of the tablet cores or granule cores, together with at least one filler-binder.
  • International Application Publication No. 2011/161689 discloses
  • pharmaceutical tablet comprising Imatinib in an amount of 50-75%w/w of the total tablet weight and comprising at least one pharmaceutically acceptable excipient without a binding agent.
  • International Application Publication No. 2011/160798 discloses pharmaceutical tablet comprising at least one pharmaceutically acceptable excipient without a binding agent.
  • U.S. Patent Application Nos. 20080226731 and 20100240672 disclose sustained release pharmaceutical compositions of Imatinib Mesylate, melt granulated with a release retardant using an extruder.
  • Imatinib free base has very low solubility in water and in aqueous solutions that are slightly alkaline.
  • the solubility of imatinib mesylate in aqueous solutions depends on pH; at pH 5.8, it is very soluble but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.
  • the aim of the present invention is to develop a new oral tablet comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient that can be produced in a simple manner.
  • the tablet according to the invention should preferably have the active ingredient present in a high amount in the tablet in order to obtain smaller tablets which are more suitable especially for patients who have problems with swallowing.
  • tablets comprising imatinib or a pharmaceutically acceptable salt thereof in an amount from more than about 80% in weight of the active moiety based on the total weight of the tablet can be prepared using conventional techniques, ensuring good storage stability throughout the shelf-life, wherein, such compositions may be prepared using any polymorphic form of imatinib mesylate.
  • the present invention provides sustained release formulations of imatinib or a pharmaceutically acceptable salt thereof for once daily administration instead of currently available twice daily administration, to further improve patient compliance.
  • aspects of the present application relate to pharmaceutical formulations comprising imatinib or its salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, and polymorphs, and mixtures thereof. Further aspects of the present application relate to processes of preparing pharmaceutical formulations comprising imatinib or its salts, together with at least one pharmaceutically acceptable excipient.
  • the application includes pharmaceutical formulations comprising imatinib mesylate in an amount from more than about 80% in weight of the active moiety based on the total weight of the tablet.
  • the application includes pharmaceutical formulations comprising imatinib mesylate, such that drug release characteristics of such formulations are maintained during storage for commercially relevant times.
  • the application includes pharmaceutical formulations comprising imatinib mesylate, wherein such formulations ensure good bioavailability by exhibiting desirable dissolution profile.
  • the application includes once daily sustained release formulations comprising imatinib mesylate and at least one release rate controlling material.
  • imatinib includes the compound imatinib, pharmaceutically acceptable salts, esters and prodrugs thereof, the active
  • Formulations can contain imatinib in the range of 5 to 1000 mg per dosage unit.
  • salts refers to salts that are known to be non-toxic and are commonly used in pharmaceutical practice. Acid salts include, for example, mineral acid salts, such as a hydrochloride,
  • Salts with organic acids include, for example, a succinate, maleate, fumarate, malate, tartrate, etc.
  • Sulfonate salts include, for example, a methanesulfonate (mesylate), benzenesulfonate, toluenesulfonate, etc.
  • Basic salts include alkali metal salts, for example a sodium salt, potassium salt, and alkaline earth metal salt, for example a calcium salt, etc.
  • imatinib and its salts can be used in any crystalline form, amorphous form, or combinations thereof.
  • imatinib or its salt can be anhydrous or in the form of hydrates, solvates, etc.
  • the application provides pharmaceutical dosage forms containing imatinib mesylate, wherein imatinib mesylate is in non-needle shaped alpha crystalline form.
  • imatinib mesylate is in micronized non- needle shaped alpha crystalline form which can be prepared using spiral jet mill for example Hosokawa Micronizer. The material after fist milling can be further milled for second and third time following the same procedure, in order to get desired particle size distribution.
  • needle shaped alpha crystalline form of imatinib mesylate can be slugged using compression machine known in the art and the obtained slugs can be milled through Qudroco mill. Material collected from Qudroco mill can be further processed using spiral jet mill to obtain non-needle shaped alpha crystalline form.
  • Various processing parameters may be manipulated to obtain desired particle size distribution.
  • the mean particle size distribution of at least 80% of the imatinib mesylate is in the range from about 1pm to about 10pm, preferably in the range from about 2 pm to about 9 pm.
  • excipient or “pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc.
  • formulation refers to dosage forms for
  • dosage forms may be solid oral dosage forms such as tablets, capsules, pills, granules, sachets, etc.
  • content uniformity refers to an assessment of how uniformly a micronized or submicron active ingredient is dispersed in a formulation. Content uniformity can be measured according to USP test method 905 "Uniformity of Dosage Units.”
  • disintegration refers to the breakdown of unit dosage forms into smaller granules or particles. Disintegration can be evaluated according to USP test method 701 "Disintegration".
  • stability for purposes of the present application relates to physical stability, chemical stability, and thermodynamic stability.
  • physical stability refers to maintenance of the polymorphic form of the drug, such as crystalline or amorphous
  • chemical stability relates to formation of drug-related impurities.
  • stability is required for commercially relevant times after manufacturing, such as for about 6, 12, 18, or 24 months, during which a product is kept in its original packaging under normal ambient conditions.
  • Stability testing frequently is conducted using storage conditions such as room temperature, e.g., 25°C and 60% relative humidity (“RH"), intermediate conditions (e.g., 30°C and 65% RH), and accelerated conditions (e.g., 40°C and 75% RH).
  • room temperature e.g., 25°C and 60% relative humidity (“RH")
  • intermediate conditions e.g., 30°C and 65% RH
  • accelerated conditions e.g., 40°C and 75% RH
  • the present application provides imatinib mesylate tablets wherein the content of Impurity 1 is not greater than about 0.15%. In embodiments, the content of Impurity 2 is not greater than about 0. 5%. In embodiments, the content of the other individual impurity is not greater than about 0.1%.
  • the content of total drug-related impurities is not greater than about 0.5%. All of these impurity contents are expressed as weight percentages of the label drug content.
  • Solid compositions of imatinib mesylate can be analyzed by common techniques, such as high performance liquid chromatography, to determine their drug content and the concentrations of drug-related impurities.
  • the application provides pharmaceutical dosage forms of imatinib having content uniformities (CU) from about 90% to about 110% by weight, with relative standard deviations (RSD) of not more than about 5%.
  • the invention relates to pharmaceutical formulations having a disintigration time of about 15 minutes.
  • pharmaceutically acceptable excipients for preparing dosage forms include, but are not limited to, any one or more of diluents, disintegrants, binders, glidants, lubricants, colouring agents, coating materials, and the like.
  • such pharmaceutically acceptable excipients may include Co- processed excipients.
  • Disintegrants may be incorporated into intragranular or extragranular blends, or both.
  • Various useful disintegrants include, but are not limited to, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium (e.g., Ac-di-solTM from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KOLLIDONTM CL from BASF (Germany), POLYPLASDONETM XL, XL10, and INF-10 from ISP Inc.
  • low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.).
  • Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, starches, and any combinations thereof.
  • Solvents that are useful in processing include, but are not limited to, water, ' methanol, ethanol, isopropanol, butanols, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,
  • Glidants or anti-sticking agents can be used, including but not limited to talc, silica derivatives, colloidal silicon dioxide, and the like, and any mixtures thereof, and lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, glyceryl monostearates, calcium stearate, zinc stearate, polyoxyethylene monostearates, fumed silicas (e.g., Aerosil® products), sucrose esters of fatty acids, polyethylene glycols, talc, sodium stearyl fumarate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats castor oils, waxes, and any combinations thereof.
  • stearic acid and stearic acid derivatives such as magnesium stearate, glyceryl monostearates, calcium stearate, zinc stearate, polyoxyethylene monostearates, fumed silicas (e.g., Aerosil
  • Various useful acidifiers include, but are not limited to, organic acids such as citric acid, acetic acid, lactic acid, malic acid, fumaric acid, or succinic acid and combinations of organic acids such as malic acid, fumaric acid, and pyruvic acid.
  • organic acids such as citric acid, acetic acid, lactic acid, malic acid, fumaric acid, or succinic acid and combinations of organic acids such as malic acid, fumaric acid, and pyruvic acid.
  • Inorganic acids such as phosphoric acid, may also be used.
  • PharmaburstTM available as three different grades like Pharmaburst B1, Pharmaburst B2, and Pharmaburst C1 , is described as "delivery system” products used by pharmaceutical industry in the production of "quick dissolve” tablets.
  • Pharmaburst B1 is composed of 85 percent mannitol (a sweetenter), 7.5 percent starch (a tabletting aid), 4.5 percent
  • Pharmaburst B2 consists of 85 percent mannitol, 10 percent polyplasdone, 5 percent sorbitol (a sweetener), and less than one percent syloid.
  • Pharmaburst CT is made of 84 percent mannitol, 16 percent polyplasdone, and less than one percent syloid.
  • F-MELT® is a co-spray dried excipient system containing 5 pharmaceutical excipients such as
  • Various filler-binders are sugars, sugar alcohols, polymeric glycosides and inorganic compounds (salts).
  • sugars are sucrose and lactose as the monohydrate or in anhydrous form.
  • sugar alcohols are mannitol, xylitol and sorbitol.
  • polymeric glycosides are maltodextrin, microcrystalline cellulose and starches of different origins, e.g. maize starch.
  • suitable salts are calcium hydrogen phosphate, calcium silicates and sodium carbonate.
  • Preferred filler-binders are calcium silicates, cellulose and starch.
  • Various useful colourants include, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, iron oxides, and any combinations thereof.
  • an outer continuous phase in the form of a film coating may be used, optionally containing additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, the like, including any combinations thereof.
  • Film-forming agents include, but are not limited to: soluble alkyl- or hydroalkyl- cellulose derivatives, for example and not limited to methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, and hydroxypropyl celluloses.
  • plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycol, triacetin, triethyl citrate and mixtures thereof.
  • a plasticizer is frequently present in an amount ranging from 5% to 30%, based on the total weight of the film coating.
  • An opacifier like titianium dioxide may also be present, in amounts ranging from about 0% to about 20%, based on the total weight of the coating.
  • Anti-adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying.
  • An example of an anti-adhesive for this purpose is talc.
  • the anti-adhesive typically is present in the film coating in an amount of about 5% to 5%, based upon the total weight of the .coating.
  • coating ingredients such as those sold as OPADRYTM (supplied by Colorcon) will be used, for example Opadry Blue 13B50579 or Opadry White OY 59800 or Opadry AMB or Opadry Orange.
  • OPADRYTM supplied by Colorcon
  • the products sold in a solid form require only mixing with a liquid before use.
  • film-forming agents may be applied as powders, using suitable powder coating equipment known in the art.
  • compositions such as tablets may be prepared using any of techniques such as dry granulation technique involving slugging or roller compaction etc., direct compression. Alternatively, granules prepared by dry granulation techniques may be filled into capsules or sachets.
  • Equipment suitable for processing pharmaceutical formulations of the present application include any one or a combination of mechanical sifters, blenders, roller compactors, granulators (rapid mixers or fluid bed granulators), fluid bed dryers, compression machines, rotating bowls or coating pans, etc.
  • Tablets prepared as above can be subjected to in vitro drug dissolution evaluations according to USP test 711 "Dissolution" to determine the rate at which the active substance is released from the dosage forms, and the content of active ingredient can conveniently be determined in solutions using techniques such as high performance liquid chromatography.
  • the application relates to sustained release formulations comprising imatinib or its salts, wherein the formulations, following dosing, can result in a reduced incidence of adverse effects and/or enhanced efficacy, when compared to an equivalent dose in an immediate release formulation.
  • sustained release dosage forms contain imatinib in the range of 5 to 1000 mg, or 20 to 800 mg, or 30 to 600 mg, or 50 to 400 mg, per dosage unit.
  • solid dosage forms may be multi-unit particulate systems comprising one portion having delayed release particles and another portion having immediate release, extended release, or combinations of immediate and extended release particles, filled into capsules or sachets or tableted into finished dosage forms.
  • sustained release formulations of the present application may be prepared by coating powders, granules, pellets, tablets, or cores with one or more functional coatings and then filling into capsules.
  • a sustained-release dosage form comprises a release rate-controlling material.
  • the rate-controlling material can be associated with the formulation either in the form of a matrix or a coating.
  • the rate-controlling material is a material that permits release of the active agent at a sustained rate into an aqueous medium.
  • the application relates to sustained-release formulations comprising imatinib or its salts and at least one release rate-controlling material, wherein a rate-controlling component is hydrophilic, hydrophobic, enteric, or combinations thereof.
  • Suitable hydrophilic materials comprise water-soluble or water swellable materials. Examples of such materials include hydroxyalkyl celluloses, hydroxyalkyl alkylcelluloses, and carboxyalkyl cellulose esters, for example, hydroxypropyl methylcelluloses (hypromelloses or HPMC), hydroxypropylcelluloses (HPC), and combinations comprising one or more of the foregoing materials.
  • the release modifying agent may be present in a matrix, or in a coating covering the matrix.
  • hydrophilic material ranges from about 5% to about 50% by weight of the formulation.
  • Suitable "hydrophobic" materials include water-insoluble neutral or synthetic waxes, fatty alcohols such as lauryl, myristyl, stearyl, cetyl, and cetostearyl alcohols, fatty acids and derivatives thereof, including fatty acid esters such as glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, stearin, palmitin, laurin, myristin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oils, cottonseed oils, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, materials having hydrocarbon backbones, and combinations comprising one or more of the for
  • EXAMPLE 1-5 Imatinib mesylate tablets prepared using dry granulation.
  • * *Opadry Orange is a formulated coating product of Colorcon, containing hypromellose 6 cP, triacetin/glycerol triacetate, titanium dioxide, and
  • Imatinib Mesylate and crospovidone or mannitol or croscarmellose sodium or sodium starch glycolate or L-HPC are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.
  • croscarmellose sodium or sodium starch glycolate or L-HPC are made in to slugs with 25 mm round punches with desirable hardness.
  • step 4 The granules from step 3 are made in to slugs second time with 25 mm round punches with desirable hardness and the slugs are milled though a QuadroTM ComilTM to obtain desirable granule size. 5.
  • Opadry Orange is dispersed in I PA and DCM.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, and then dried.
  • Tablets prepared of Examples 1 and 2 are packaged in closed HDPE containers, together with desiccant canister, and stored at three different conditions: 25°C and 60% relative humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and 75% RH (Condition 3) for one month. Dissolution testing results of initial and stored samples are shown in Table 1 and Table 2 respectively. The dissolution study is conducted in 1000 mL of 0.1 N HCI medium, using USP type 2 apparatus, while stirred at 50 rpm for 30 minutes.
  • IPA Isopropyl alcohol
  • Opadry AMB is a formulated coating product of Colorcon, containing polyvinyl alcohol, lecithin, soy, xanthan gum, polyethylene glycol (PEG 3350), titanium dioxide, talc, and pharmaceutically acceptable pigment.
  • Non-coating ingredients except for colloidal silicon dioxide and sodium stearyl fumarate, are sifted through a #30 mesh sieve and blended.
  • Colloidal silicon dioxide and sodium stearyl fumarate previously passed through a #60 mesh sieve, is mixed with the blend from step 1 , and then the mixture is compressed into tablets.
  • Opadry AMB is dispersed in IPA and DCM.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, then dried.
  • lubricated granules prepared in Examples 1-5 or a lubricated blends prepared in Example 6-9 are filled into capsules of suitable size.
  • Imatinib mesylate is sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.
  • step 2 The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.
  • the granules are blended with extra granular material (Sifted sod i um stearyl fumarate) for 3 minutes.
  • the lubricated blend is compressed with the suitable size punches .
  • Imatinib mesylate and crospovidone are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh s i eve.
  • step 2 Sifted imatinib mesylate and Sodium Stearyl fumarate are transferred into the blender and blended for 3 minutes. 3. The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.
  • the lubricated blend is compressed with the suitable size punches.
  • imatinib mesylate, sodium starch glycolate, colloidal silicon dioxide and citric acid are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate i s sifted through a #60 mesh sieve.
  • step 2 The blended material of step 2 is made in to slugs with 25 mm round punches with desirable hardness.
  • the lubricated blend is compressed with the suitable size punches.
  • Dissolution testing results of tablets of Examples 11 , 13 and 15 are shown in Table 3.
  • the dissolution study is conducted in 900 mL of 6.8 pH phosphate buffer medium, using (JSP type 2 apparatus, while stirred at 50 rpm for 30 minutes.
  • Imatinib mesylate, crosspovidone and colloidal silicon dioxide are sifted through a #30 mesh sieve, whereas sodium stearyl fumarate is sifted through a #60 mesh sieve.
  • Sifted imatinib mesylate is slugged using round flat punches 25mm using tablet compression machine with desired hardness.
  • the lubricated blend is compressed with the suitable size punches.
  • Imatinib mesylate and Kollidon SR were blended for 5 min at 20 rpm in a double cone blender.
  • Ethyl cellulose was added and blended for 5 min at 20 rpm, with the blend prepared in step 2.
  • Opadry AMB is dispersed in IPA and DCM.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, and then dried.
  • Imatinib mesylate and hypromellose K 100M were blended for 5 min at 20 rpm in a double cone blender.
  • Opadry AMB is dispersed in IPA and DCM.
  • Tablets are coated with the dispersion of step 1 in a coating pan at 40- 50°C, and then dried.
  • Dissolution testing results of tablets of Examples 25-28 are shown in Table 4.
  • the dissolution study is conducted in 900 mL of 0.1 N HCI medium, using USP type 2 apparatus, while stirred at 00 rpm for 2 hours.

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne, dans certains aspects, des formulations pharmaceutiques comprenant l'imatinib ou ses sels, isomères, racémates, énantiomères, hydrates, solvates, métabolites, polymorphes, et leurs mélanges. D'autres aspects concernent des procédés de préparation de formulations pharmaceutiques comprenant l'imatinib ou ses sels, ainsi qu'au moins un excipient pharmaceutiquement acceptable.
PCT/IN2012/000488 2011-07-11 2012-07-11 Formulations d'imatinib WO2013008253A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014139836A1 (fr) * 2013-03-15 2014-09-18 Pharmaceutical Oriented Services Ltd Compositions pharmaceutiques à base d'imatinib
EP2803352A1 (fr) * 2013-05-14 2014-11-19 Hetero Research Foundation Compositions d'imatinib
WO2021009686A1 (fr) * 2019-07-15 2021-01-21 Intas Pharmaceuticals Ltd. Composition pharmaceutique d'imatinib
TWI794214B (zh) * 2017-03-08 2023-03-01 日商武田藥品工業股份有限公司 包含5-氯-n4-[2-(二甲基磷醯基)苯基]-n2-{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}嘧啶-2,4-二胺之醫藥調配物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY148074A (en) * 2005-05-10 2013-02-28 Novartis Ag Pharmaceutical compositions comprising imatinib and a release retardant
KR20080017067A (ko) * 2005-06-03 2008-02-25 엘란 파마 인터내셔널 리미티드 나노입자형 이마티닙 메실레이트 제제
EP2068835A2 (fr) * 2006-09-01 2009-06-17 Teva Pharmaceutical Industries Ltd. Compositions d'imatinib

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014139836A1 (fr) * 2013-03-15 2014-09-18 Pharmaceutical Oriented Services Ltd Compositions pharmaceutiques à base d'imatinib
EP2803352A1 (fr) * 2013-05-14 2014-11-19 Hetero Research Foundation Compositions d'imatinib
EP2803353A1 (fr) * 2013-05-14 2014-11-19 Hetero Research Foundation Compositions d'imatinib
TWI794214B (zh) * 2017-03-08 2023-03-01 日商武田藥品工業股份有限公司 包含5-氯-n4-[2-(二甲基磷醯基)苯基]-n2-{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}嘧啶-2,4-二胺之醫藥調配物
WO2021009686A1 (fr) * 2019-07-15 2021-01-21 Intas Pharmaceuticals Ltd. Composition pharmaceutique d'imatinib

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